MIG-23 is involved in sperm migration in Ascaris suum

Sperm motility acquisition during maturation is essential for successful fertilization.Extracellular adenosine-5'-triphosphate (ATP) level mediation by MIG-23, which is a homolog of human ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase), was required for major sperm protein filament dynamics and sperm motility in the nematode Ascaris suum. MIG-23 was localized on the sperm plasma membrane. During sperm activation, mitochondrial activity was increased dramatically, and a large amount of ATP was produced and stored in refringent granules (RGs). In addition, a portion of the produced ATP was released to the extracellular space through ATP channels, which were composed of innexins and localized on the sperm plasma membrane. Spermatozoa, instead of spermatids, hydrolyzed exogenous ATP and processed ecto-ATPase activity. MIG-23 contributed to the ecto-ATPase activity of spermatozoa. MIG-23 activity was interrupted, spermatozoa also decreased their ATP hydrolysis activity. Blocking MIG-23 activity resulted in an increase in the depolymerization rate of MSP filaments in pseudopodia, which eventually affected nematode sperm migration. Overall, our data imply that MIG-23, which contributes to the ecto-ATPase activity of spermatozoa, regulates sperm migration by modulating extracellular ATP levels.

E-NTPDases: Possible Roles on Host-Parasite Interactions and Therapeutic Opportunities

Belonging to the GDA1/CD39 protein superfamily, nucleoside triphosphate diphosphohydrolases (NTPDases) catalyze the hydrolysis of ATP and ADP to the monophosphate form (AMP) and inorganic phosphate (Pi). Several NTPDase isoforms have been described in different cells, from pathogenic organisms to animals and plants. Biochemical characterization of nucleotidases/NTPDases has revealed the existence of isoforms with different specificities regarding divalent cations (such as calcium and magnesium) and substrates. In mammals, NTPDases have been implicated in the regulation of thrombosis and inflammation. In parasites, such as Trichomonas vaginalis, Trypanosoma spp., Leishmania spp., Schistosoma spp. and Toxoplasma gondii, NTPDases were found on the surface of the cell, and important processes like growth, infectivity, and virulence seem to depend on their activity. For instance, experimental evidence has indicated that parasite NTPDases can regulate the levels of ATP and Adenosine (Ado) of the host cell, leading to the modulation of the host immune response. In this work, we provide a comprehensive review showing the involvement of the nucleotidases/NTPDases in parasites infectivity and virulence, and how inhibition of NTPDases contributes to parasite clearance and the development of new antiparasitic drugs.

Actinosomes: condensate-templated proteinaceous containers for engineering synthetic cells

Engineering synthetic cells has a broad appeal, from understanding living cells to designing novel biomaterials for therapeutics, biosensing, and hybrid interfaces. A key prerequisite to creating synthetic cells is a functional three-dimensional container capable of orchestrating biochemical reactions. In this study, we present an easy and effective technique to make cell-sized porous containers crafted using the interactions between biomolecular condensates and actin cytoskeleton - we coin them actinosomes. This approach uses polypeptide/nucleoside triphosphate condensates and localizes actin monomers on their surface. By triggering actin polymerization at the expense of sequestered ATP and using osmotic gradients, the condensates are structurally transformed into containers with the boundary made up of actin filaments and polylysine polymers. We show that the GTP-to-ATP ratio is a crucial parameter for forming actinosomes: insufficient ATP prevents condensate dissolution while excess ATP leads to undesired crumpling. The surface of actinosomes lacks any structural order and is porous. We show the functionality of the actinosomes by using them as bioreactors capable of protein synthesis. Actinosomes are a handy addition to the synthetic cell platform, with appealing properties like ease-of-production, inherent encapsulation capacity, and an active surface which holds the potential to trigger signaling cascades and form multicellular assemblies, with potential for medical and biotechnological applications.

ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

Stem cell derived beta-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably to mature adult beta cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human beta cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within <i>in vitro</i> cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the self-enriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 (NDPTase3)) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of <i>in vitro</i> sBC maturation and provide important insights towards developing functionally mature sBC for diabetes cell replacement therapy.

ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

Stem cell derived beta-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably to mature adult beta cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human beta cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within <i>in vitro</i> cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the self-enriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 (NDPTase3)) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of <i>in vitro</i> sBC maturation and provide important insights towards developing functionally mature sBC for diabetes cell replacement therapy.

ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

Stem cell derived beta-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably to mature adult beta cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human beta cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within <i>in vitro</i> cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the self-enriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 (NDPTase3)) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of <i>in vitro</i> sBC maturation and provide important insights towards developing functionally mature sBC for diabetes cell replacement therapy.

ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

Stem cell derived beta-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably to mature adult beta cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human beta cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within <i>in vitro</i> cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the self-enriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 (NDPTase3)) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of <i>in vitro</i> sBC maturation and provide important insights towards developing functionally mature sBC for diabetes cell replacement therapy.

Brief review on remdesivir

Remdesivir is an investigational broad-spectrum small-molecule antiviral drug that has confirmed interest in the direction of RNA viruses in numerous families, which encompass Coronaviridae (alongside aspect SARS-CoV, MERS-CoV, and lines of bat coronaviruses able to infecting human respiratory epithelial cells), Paramyxoviridae (alongside aspect Nipah virus, respiratory syncytial virus, and Hendra virus), and Filoviridae (alongside aspect Ebola virus). Originally superior to cope with Ebola virus infection , remdesivir is a prodrug of the determine adenosine analog, each of which can be metabolized into an energetic nucleoside triphosphate (NTP) via the host. The determine nucleoside, GS-441524, has displayed antiviral interest within the direction of SARS-CoV, Marburg virus , and pussycat infectious peritonitis virus, amongst others. A fashion of research have tested the effects of these pills on coronaviruses (CoVs) each in vitro and in vivo the use of mouse and non-human primate animal models.

ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential

On 11 March 2020, the World Health Organization (WHO) classified the Coronavirus Disease 2019 (COVID-19) as a global pandemic, which tested healthcare systems, administrations, and treatment ingenuity across the world. COVID-19 is caused by the novel beta coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the inception of the pandemic, treatment options have been either limited or ineffective. Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Remdesivir is an adenosine nucleotide analog prodrug that is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). The active nucleoside triphosphate metabolite is incorporated into the SARS-CoV-2 RNA viral chains, preventing its replication. The lack of reported drug development and characterization studies with remdesivir in public domain has created a void where information on the absorption, distribution, metabolism, elimination (ADME) properties, pharmacokinetics (PK), or drug-drug interaction (DDI) is limited. By understanding these properties, clinicians can prevent subtherapeutic and supratherapeutic levels of remdesivir and thus avoid further complications in COVID-19 patients. Remdesivir is metabolized by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases. In this narrative review, we have evaluated the currently available ADME, PK, and DDI information about remdesivir and have discussed the potential of DDIs between remdesivir and different COVID-19 drug regimens and agents used for comorbidities. Considering the nascent status of remdesivir in the therapeutic domain, extensive future work is needed to formulate safer COVID-19 treatment guidelines involving this medication.